The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. The current focus is on mechanisms of signal transduction. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ralpha, IL-2Rbeta, and gamma-c. Dr. Leonard cloned IL-2Ralpha as a postdoctoral fellow in 1984, and his group discovered IL-2Rbeta in 1986 and reported in 1993 that mutation of the gamma-c chain results in X-linked severe combined immunodeficiency (XSCID) in humans. Having previously shown gamma-c associates with the Janus family tyrosine kinase Jak3, the group has now reported a patient with an inactivating Jak3 mutation that causes an autosomal recessive form SCID indistinguishable for XSCID. This suggest that at least for development, all gamma-c- dependent signals are dependent on Jak3 and conversely that Jak3 is only involved in transducing signals induced via gamma-c- dependent cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15). To further clarify the role of gamma-c, the yeast two- hybrid system has been used to identify proteins that can interact with gamma-c. In the previous year, the group created a gamma-c knockout mouse and observed an age-dependent peripheral CD4+T cell expansion; the basis for this finding has now been clarified. Studies are planned to use the mice as an animal target for studies oriented towards gene therapy of XSCID. In contrast to diminished Jak-STAT signaling in XSCID, we had previously shown the Jak-STAT pathways that normally are induced by IL-2 were constitutively activated T-cells transformed with HTLV-I. It has now been shown that similar constitutively activated pathways are found in IL-6-independent abl/myc-induced tumors, but not in IL-6-dependent raf/myc tumors, a finding with implications for myelomas. Finally, in the past year, the group has clarified signaling domains of IL-2Rbeta. Tyrosine 338 (Y338) of IL-2Rbeta mediates Shc docking and phosphorylation, whereas Y392 and Y510 mediate STAT protein activation. Together, these 3 tyrosines mediate maximal IL-2-induced proliferation, whereas suboptimal proliferation was seen when any one of them. Thus, these tyrosines couple to at least 2 signaling pathways to mediate maximal IL-2-induced proliferation. Additional IL-2 signaling pathways, including the role of PI 3-K have been studied. Although Jak3 primarily associates with gamma-c, it can also associate with IL-2Rbeta. The mechanism by which Jak3 can associate with IL-2Rbeta has been further clarified. Finally, a receptor component of the human IL-4 and IL-13 receptors has been cloned. Overall, these studies clarify signaling pathways in normal T-cells, in SCID, and enhance our understanding of cellular transformation.